The TIM-3 gene family consists of eight genes in mouse and three genes in human, and each of these genes are located at chromosome 11 and at chromosome 5q33. These gene regions are known to be related with autoimmune diseases and allergic diseases. TIM protein is a type I transmembrane protein having a structurally conserved immunoglobulin variable (IgV) domain and a mucin domain.
TIM protein was considered to be specifically expressed on T cells and directly regulated the T cell activity, but there are also reports on expression of TIM3 protein in antigen-presenting cells and on their functions. According to the crystal structure analysis, the TIM protein has a conserved protein structure and has a ligand binding site in an IgV domain.
TIM3 was identified as a molecule specifically expressed on mouse Th1 cells but not on Th2 cells. The DNA sequence, the amino acid sequence and the three-dimensional structure of TIM3 is available in the public data base such as the GenBank accession number NM_032782 and NM_134250. TIM-3 is also known as HAVCR2.
In humans, as similar to mice, TIM3 is expressed on T-cells as well as phagocytic cells such as macrophages and dendritic cells. Binding of TIM3 to a protein ligand (e.g., galectin-9) can inhibit the Th1 response via mechanism of apoptosis induction, and therefore lead to such as induction of peripheral tolerance.
The reduction in expression of human TIM3 with siRNA or the inhibition of human TIM3 by blocking-antibody increased the secretion of interferon γ (IFN-γ) from CD4 positive T-cells, supporting the inhibitory role of TIM-3 in human T cells. In phagocytes, TIM3 also functions as a receptor for recognizing the apoptosis cells.
Analysis of clinical samples from autoimmune disease patients showed no expression of TIM3 in CD4 positive cells. In particular, in T cell clones derived from the cerebrospinal fluid of patients with multiple sclerosis, the expression level of TIM3 was lower and the secretion level of IFN-γ was higher than those of clones derived from normal healthy persons.
According to the microarray analysis of hematopoietic stem cells from acute myeloid leukemia (hereinafter referred to as “AML”) patients and normal hematopoietic stem cells, TIM3 is expressed on AML stem cells and therefore the analysis suggested involvement of TIM3 in hematological malignancy. Examples of the anti-TIM3 monoclonal antibodies which were established up to now include anti-human TIM-3 rat monoclonal antibody (Clone 344823, manufactured by R&D Systems) and anti-human TIM-3 mouse monoclonal antibody (Clone F38-2E2, manufactured by R&D Systems). Therefore, there is a need in the art for fully human anti-TIM3 antibodies.